A central goal of neurobiology is to understand how the brain forms, stores, retrieves and encodes information and how these operations go awry in disease. The focus of this application is astrocytes, which make intimate contacts with neurons throughout the brain. Long considered simply the brain's glue, astrocytes are emerging as important regulators of neuronal function. Deciphering the roles of astrocytes in the brain is considered one of the major open questions in neuroscience. This Pioneer Award application seeks to test the novel hypothesis that an early step in brain disorders involves dysfunction of the very fine termini of astrocytes called branchlets that are known to abut synapses. In this context, we define dysfunction as branchlet withdrawal from synapses or altered branchlet signaling, including trophic support, to synapses. These dysfunctions would alter established astrocyte functions including neurotransmitter clearance, synapse regulation and maintenance. This in turn would alter the timing of synaptic transmission, contribute to excitotoxicity and perhaps trigger synapse removal. By focusing on the striatal microcircuitry, we will test the hypothesis that branchlets represents a hitherto overlooked mechanism in neurological and psychiatric disorders that could be exploited for novel therapeutics.